Most human diseases result from the interplay of hereditary and environmental factors. The nature of the genetic component in common disorders is a subject of some debate. There are proponents for a model in which a few common genetic variants have weak effects, which add up to a significant attributable genetic risk. On the other hand it is possible that many different rare genetic mutations, each with a strong effect, in aggregate account for disease in a high proportion of people. An ongoing project supported by the Yale Skin Cancer SPORE Grant involves analysis of the roles of hereditary and environmental factors and the interaction between these factors in the risk for early-onset basal cell carcinoma of the skin (below age 40). The SPORE supports collection of broad demographic, ethnic, and environmental risk factor data as well as DNA samples from 500 cases and 500 controls. Sequencing of MC1R, a small (one-exon) skin pigment gene in all subjects is also supported. At the time the study was conceived, the cost of analysis of additional genes was prohibitively expensive. More recent introduction of high- throughput platforms for DNA sequencing will allow for querying many genes for mutations that may be associated with skin cancer risk. The aim of this application is use high-throughput platforms for sequencing constitutional DNA from 100 cases and 100 controls. This project will cast a wide net, examining all known major skin pigment genes, all genes closely associated with repair of UV-induced DNA damage, and circadian rhythm genes that may be associated with cancer risk. The intention is to generate preliminary data from this subset of study subjects to support applications for future large grants that would allow us to test all of our subjects for promising candidate genes and, in collaboration with other groups, examine these genes in additional skin cancer cases. Discovering an underlying genetic predisposition may help tailor preventive measures and "personalize" medical treatment. The well established role of UV exposure as an environmental risk factor for skin cancer provides a route to translate our analyses into public health approaches to better prevent skin cancer. In theory, individuals with a genetic predisposition to this cancer type could be targeted for behavior modification. PUBLIC HEALTH RELEVANCE: Discovering an underlying genetic predisposition to skin cancer may help tailor preventive measures and "personalize" medical treatment. The well established role of UV exposure as an environmental risk factor for skin cancer provides a route to translate our analyses into public health approaches to better prevent skin cancer. In theory, individuals with a genetic predisposition to this cancer type could be targeted for behavior modification.